Non-Insulin-Dependent Diabetes Mellitus (NIDDM) has a predominant genetic component as is evident from high concordance rates in monozygotic twins and marked family and racial aggregation. While most data suggest a golygenic mode of inhertance with genetic heterogeneity, diabetogenic genes have not been identified in the vast majority of NIDDM patients. Several major metabolic abnormalities contribute to the NIDDM phenotype; insulin reistance is instrumental in the transition from normal to Impaired Glucose Tolerance (IGT), and further deterioration to overt diabetes depends upon insulin secretory failure as a consequence of prolonged hyperglycemic stress ("glucose toxicity"). In addition, obesity is an independent risk factor for developing NIDDM and has a genetic basis independent from that causing insulin resistance. Therefore, insulin resistance, insulin secretory failure, and obesity may be determined by subsets of genes which contribute to the polygenic basis of NIDDM, and constitute more proximal or refined phenotypes for diabetogenic genes. Our overall goal in the proposed studies is to identify genetic markers for NIDDM and pre-diabetic phenotypic characteristics such as insulin resistance and obesity.